Deep Vein Thrombosis Treatment With the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients Using a Strong CYP 3A4 Inducer

NCT00786422 | Completed Phase 2 Results DMC

• 2 other identifiers: 132382008-003303-31
• Study Type: interventional
• Target: 25
• Locations: 8 countries
• Sites: 15

Brief Summary

This is a multicenter, cohort study evaluating an adapted rivaroxaban dose regimen in patients with acute, proximal deep-vein thrombosis (DVT) or acute pulmonary embolism (PE) who concomitantly use a strong cytochrome P450 isoenzyme 3A4 (CYP 3A4) inducer for the entire 3-month study duration.

Conditions

Venous Thrombosis; Deep Vein Thrombosis

Keywords

Embolism and Thrombosis; Pulmonary Embolism; Embolism; Venous Thrombosis; Thrombosis; Enzyme Inducers; CYP Inducers; Cohort Study; Pharmacologic Actions; Respiratory Tract Diseases; Lung Diseases; Vascular Diseases; Human Immunodeficiency Virus (HIV); Neurologic disease; Additional relevant MeSH terms:; Fibrin Modulating Agents; Anticoagulants; Therapeutic Uses; Hematologic Agents; Enzyme Inhibitors; Cardiovascular Diseases; Cardiovascular Agents

Outcome Measures

Primary Outcomes (6)

• Pharmacodynamics - Prothrombin Time (PT), Baseline Value

  Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Mean and standard deviation (SD) values are presented for PT baseline.

  The baseline value of prothrombin time is measured or calculated at a rivaroxaban concentration of 0 µg/L and is based on the observations that were made during the 3 months treatment period

• Pharmacodynamics - Prothrombin Time (PT), Slope

  Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out of PT is in seconds. The PT slope describes the linear increase of PT for one unit increase in concentration, thus the unit of PT slope is s\*(µg/L)\^-1. The final population PK/PD model included a fixed slope that was fitted to the data of the 19 patients that were eligible for evaluation. The estimated mean value (fixed/ the same for all patients in this study) is presented for PT slope.

  Up to 3 months treatment

• Pharmacokinetics - AUC(0-24)ss (Area Under the Measurement Versus Time Curve From Time 0 to 24 Hours After First Dosing on a Day at Steady State) of Rivaroxaban

  AUC(0-24)ss was predicted from rivaroxaban plasma concentrations for each individual participant and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inducer.

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

• Pharmacokinetics - Cmax,ss (Maximum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban

  Cmax,ss was predicted from rivaroxaban plasma concentrations for each individual participant and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong CYP3A4 inducer.

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

• Pharmacokinetics - Cmin,ss (Minimum Observed Drug Concentration in Measured Matrix at Steady State During a Dosage Interval) of Rivaroxaban

  Cmin,ss was predicted for each individual participant from rivaroxaban plasma concentrations and was only considered for the time period during which participants concomitantly received rivaroxaban and a strong CYP3A4 inducer.

  0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

• Percentage of Participants With Clinically Relevant Bleeding (i.e. Major Bleeding and Clinically Relevant Non-major Bleeding)

  All events were adjudicated and confirmed by a central independent adjudication committee. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life.

  Up to 3 months treatment and during subsequent 2 days

Secondary Outcomes (4)

• Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Non-fatal or Fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment

  Up to 3 months treatment and during subsequent 30-day observational period for an individual participant

• Percentage of Participants With All Deaths

  Up to 3 months and on-treatment (up to 2 days after stop of study drug) plus an observational period planned for one month

• Percentage of Participants With Treatment Emergent Deaths - 7 Days Window

  Up to 3 months treatment and during subsequent 7 days

• Percentage of Participants With Other Vascular Events

  Up to 3 months treatment and during subsequent 1 day

Study Arms (1)

Rivaroxaban (Xarelto, BAY59-7939)

EXPERIMENTAL

Drug: Rivaroxaban (Xarelto, BAY59-7939)

Interventions

Rivaroxaban (Xarelto, BAY59-7939) DRUG

Participants received 30 mg rivaroxaban bid (twice-daily) orally for the first 3 weeks followed by 20 mg rivaroxaban bid for the remainder of the 3-month treatment period.

Rivaroxaban (Xarelto, BAY59-7939)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed acute symptomatic proximal deep- vein thrombosis and/or pulmonary embolism
• Concomitant use of a strong CYP 3A4 inducer, (i.e., carbamazepine, phenytoin, rifampicin/rifampin, and rifabutin)

You may not qualify if:

• Legal lower age limitations (country specific)
• Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of deep -vein thrombosis and/or pulmonary embolism
• Other indication for vitamin K antagonist (VKA) than deep -vein thrombosis and/or pulmonary embolism
• Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic ketoconazole)
• Use of the strong CYP 3A4 inducers phenobarbital/primidone or St John's Wort

Sponsors & Collaborators

• Bayer: lead
• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: collaborator

Study Sites (16)

Unknown Facility

Redcliffe, Queensland, 4020, Australia

Location

Unknown Facility

Vienna, Vienna, 1090, Austria

Location

Unknown Facility

São Paulo, São Paulo, 01323-001, Brazil

Location

Unknown Facility

München, Bavaria, 80331, Germany

Location

Unknown Facility

Debrecen, 4032, Hungary

Location

Unknown Facility

Ashkelon, 7830604, Israel

Location

Unknown Facility

Holon, 58100, Israel

Location

Unknown Facility

Pavia, 27100, Italy

Location

Unknown Facility

Amsterdam, 1105 AZ, Netherlands

Location

Unknown Facility

Johannesburg, Gauteng, 2132, South Africa

Location

Unknown Facility

Johannesburg, Gauteng, 2193, South Africa

Location

Unknown Facility

Pretoria, Gauteng, 0084, South Africa

Location

Unknown Facility

Pretoria, Gauteng, 0157, South Africa

Location

Unknown Facility

Roodepoort, Gauteng, 1724, South Africa

Location

Unknown Facility

Somerset West, Western Cape, 7130, South Africa

Location

Unknown Facility

Worcester, Western Cape, 6850, South Africa

Location

Related Links

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MeSH Terms

Conditions

Venous Thrombosis; Embolism and Thrombosis; Pulmonary Embolism; Embolism; Thrombosis; Respiratory Tract Diseases; Lung Diseases; Vascular Diseases; Acquired Immunodeficiency Syndrome; Cardiovascular Diseases

Interventions

Rivaroxaban

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: BAYER

clinical-trials-contact@bayerhealthcare.com

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2008
• First Posted: November 6, 2008
• Study Start: May 1, 2009
• Primary Completion: May 1, 2011
• Study Completion: June 1, 2011
• Last Updated: November 18, 2015
• Results First Posted: June 13, 2014

Record last verified: 2015-10

Locations

DE (1); HU (1); IL (2); AU (1); BR (1); IT (1); NL (1); ZA (7)